Repeated cycles of muscle degeneration/regeneration can exacerbate tissue decline in conditions such as muscular dystrophy and sarcopenia. This decline can occur via molecular/cellular processes involving select cytokines and/or muscle stem cells (i.e., satellite cells, SCs). In rhabdomyosarcoma (RMS), a highly metastatic and often deadly soft tissue childhood sarcoma, tumors typically arise in muscle and show histopathological features of chronic damage more common to sites of muscle regeneration. Based on these observations and our recently published findings, chronic activation of SCs is implicated as playing a functional role in fostering neoplastic progression of RMS. Our experimental data include that: (i) SCs facilitate tumor engraftment in an interleukin (IL)-4 Receptor (IL4R?)-dependent manner, (ii) IL4R?-blockade significantly curtails lymphatic and hematogenous metastases, and (iii) SCs fusion to RMS cells is also IL4R?-dependent, the functional significance of which is yet unknown. That said, with regard to the latter, fused cells in murine RMS models are strongly reminiscent of multinucleated, differentiated yet proliferative (Ki67+) rhabdomyoblasts found in human RMS. Given that similar multinucleated cells are tumor-propagating in other forms of sarcoma, we hypothesize that IL4R? blockade will prevent new RMS engraftment, metastases and relapse by interfering with RMS-SC interactions and thus represent an efficacious therapeutic strategy for children with RMS. In response to the pressing clinical need of children with this disease for new agents, our overall goal here is not only to identify functionally significant mechanisms regulating RMS progression, but to also translate this knowledge into a feasible therapeutic strategy for RMS intervention in partnership with Children's Oncology Group cooperative trial investigators. Thus, taking a combined muscle and tumor biology approach using state-of-the-art genetic murine RMS models and human RMS culture models, we will: (Aim 1) Delineate contribution of SC-tumor cell fusion to RMS progression, and reveal functional significance of IL4R? as well as CCL-CCR chemotaxis for cell fusion. These studies will define tumorigenic properties (engraftment, metastasis, chemotherapy-radiation resistance) of experimentally-generated, multinucleated SC-RMS fused cells. (Aim 2) We will determine the functional contribution of IL4R? signaling in infiltrating host cells, SCs and malignant RMS cells to disease progression. These genetic studies will define significance of IL4R? signaling in SCs, RMS cells, and stromal cells (macrophages, fibroblasts, fibrocyte- adipocyte progenitors) in the RMS tumor microenvironment, and (Aim 3). We will evaluate the IL4R? signaling cascade as a preclinical therapeutic target in RMS with a clinical-grade reagent, e.g., REGN668. In the end, results from these studies will define functional mechanisms regulated by IL4Ra signaling is RMS that can be rapidly translated to the clinic.